PROJECT SUMMARY This program aims to develop a novel, non-opioid therapeutic for the treatment of pain that targets a subtype of the human voltage-gated Na+ ion channel, NaV1.7. Preliminary data indicate that SiteOne's lead drug candidates may be more effective than opioids for treating certain types of pain, and lack the side effects associated with opioid analgesics, which include nausea, drowsiness, respiratory depression and potential for addiction. Voltage-gated Na+ ion channels are integral membrane proteins responsible for the transmission of signals along electrically conducting cells. Ten mammalian genes have been sequenced, which encode ten distinct channel isoforms (NaV1.1-1.9 and NaX), each having unique gating properties, and cellular and tissue distribution patterns. Recent studies have correlated a hereditary loss-of-function mutation in one human Na+ channel isoform ? NaV1.7 ? with a rare genetic disorder known as Congenital Insensitivity to Pain (CIP). Individuals with CIP have reduced sensitivity to normally painful stimuli without significant deficits to sensory or cognitive function. A compelling body of evidence indicates that selective inhibition of NaV1.7 in normal humans could recapitulate the phenotype of CIP. However, the high homology of human NaV proteins, coupled with challenges associated with high-throughput screening against multiple ion channel targets, have thwarted most efforts to develop selective antagonists for individual NaV subtypes. SiteOne has identified a small collection of drug candidates that exhibit 100 to 2000-fold selectivity for inhibition of human NaV1.7 over other peripheral human NaV isoforms. During Phase I and Phase II of our program, lead drug candidates were discovered by leveraging a two amino acid variation in the pore region of NaV1.7 that is not present in any other human NaV isoform. These compounds have been advanced through a series of in vitro and in vivo pharmacology, pharmacokinetic, safety and efficacy studies. During Phase IIB of our program, we aim to improve the synthetic route to a single lead drug candidate, manufacture multi-hundred gram quantities of this compound, and complete characterization, pharmacology and safety studies in support of an Investigational New Drug application. Success of this program will lead to the filing of an IND and support advancement of a novel, selective inhibitor of NaV1.7 into clinical testing.